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PUBLIC RELEASE SUMMARY

on the Evaluation of the New Active Monepantel in the Product ZolvixMonepantel Broad Spectrum Oral Anthelmintic for Sheep

APVMA Product Number 62752

JUNE 2010


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Commonwealth of Australia 2010

This work is copyright. Apart from any use permitted under the Copyright Act 1968, no part may be reproduced without

permission from the Australian Pesticides & Veterinary Medicines Authority. Requests and inquiries concerning reproduction

and rights can be made to:

The Manager, Public Affairs

Australian Pesticides and Veterinary Medicines Authority

PO Box 6182

KINGSTON ACT 2604

Australia

Email: [email protected]

This document is published by the APVMA. In referencing th is document the APVMA should be cited as both author and

publisher.

ISSN: 1443-1335

Website: This publication is available from the APVMA website: http://www.apvma.gov.au

Comments and enquiries may be directed to:

Contact Officer

Veterinary Medicines Program

Australian Pesticides & Veterinary Medicines Authority

PO Box 6182

KINGSTON ACT 2604

Australia

Telephone: +61 2 6210 4700

Fax: +61 2 6210 4776

Email: #[email protected]
mailto:[email protected]://www.apvma.gov.au/http://www.apvma.gov.au/mailto:[email protected]


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CONTENTS iii

CONTENTS

PREFACE V

About this document v

Making a submission v

Further information vi

1 INTRODUCTION 1

2 CHEMISTRY AND MANUFACTURE 2

2.1

ACTIVE CONSTITUENT 2

2.2 PRODUCT 3

2.3 RECOMMENDATION 3

3 TOXICOLOGICAL ASSESSMENT 5

3.1 EVALUATION OF TOXICOLOGY 5

3.2 PUBLIC HEALTH STANDARDS 9

4 RESIDUES ASSESSMENT 10

4.1 INTRODUCTION 10

4.2 DATA PROVIDED 104.3 EVALUATION SUMMARY 10

4.4 CONCLUSIONS AND RECOMMENDATIONS 15

5 ASSESSMENT OF OVERSEAS TRADE ASPECTS OF RESIDUES IN FOOD 17

6 OCCUPATIONAL HEALTH AND SAFETY ASSESSMENT 20

6.1 HEALTH HAZARDS 20

6.2 FORMULATION, PACKAGING, TRANSPORT, STORAGE AND RETAILING 20

6.3 USE PATTERN 20

6.4 EXPOSURE DURING USE 20

6.5 EXPOSURE DURING RE-ENTRY 21

6.6 RECOMMENDATIONS FOR SAFE USE 21

6.7 CONCLUSION 21

7 ENVIRONMENTAL ASSESSMENT 22

7.1 INTRODUCTION 22

7.2 ENVIRONMENTAL CHEMISTRY AND FATE 22

7.3 ENVIRONMENTAL EFFECTS 23

7.4 PREDICTION OF ENVIRONMENTAL RISK 24

7.5 CONCLUSION 25


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iv PUBLIC RELEASE SUMMARY [PRODUCT NAME]

8 EFFICACY AND SAFETY ASSESSMENT 27

8.1 EVALUATION OF EFFICACY DATA 27

8.2 EVALUATION OF TARGET ANIMAL SAFETY DATA 29

8.3 CONCLUSIONS 31

9 LABELLING REQUIREMENTS 32

ABBREVIATIONS 75

GLOSSARY 78

REFERENCES 79

LIST OF TABLESTable 1: The Limits of Quantification (LOQs) and Limits of Detection (LODs) for the analytical method 12

Table 2: MRL Standard - Table 1 Amendments 16

Table 3: MRL Standard Table 3 Amendments 16

Table 4: Comparison of the recommended Australian and overseas monepantel MRLs/tolerances 18


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PREFACE v

PREFACE

The Australian Pesticides and Veterinary Medicines Authority (APVMA) is an independent statutory authority

with responsibility for assessing and approving agricultural and veterinary chemical products prior to their

sale and use in Australia.

In undertaking this task, the APVMA works in close cooperation with advisory agencies, including the

Department of Health and Aging, Office of Chemical Safety and Environmental Health (OCSEH), Department

of the Environment, Water, Heritage and the Arts (DEWHA), and State Departments of Primary Industry.

The APVMA has a policy of encouraging openness and transparency in its activities and of seeking

community involvement in decision making. Part of that process is the publication of public release

summaries for all products containing new active ingredients.

The information and technical data required by the APVMA to assess the safety of new chemical products

and the methods of assessment must be undertaken according to accepted scientific principles. Details are

outlined in the APVMAs publication VetMORAG: Manual of Requirements and Guidelines.

This Public Release Summary is intended as a brief overview of the assessment that has been completed by

the APVMA and its advisory agencies. It has been deliberately presented in a manner that is likely to be

informative to the widest possible audience thereby encouraging public comment.

About this document

This is a Public Release Summary.

It indicates that the Australian Pesticides and Veterinary Medicines Authority (APVMA) is considering an

application for registration of an agricultural or veterinary chemical. It provides a summary of the APVMAs

assessment.

Comment is sought from industry groups and stakeholders on the information contained within this

document.

Making a submission

In accordance with sections 12 and 13 of the Agvet Code, the APVMA invites any person to submit a

relevant written submission as to whether the application for registration of Zolvix Monepantel Broad

Spectrum Oral Anthelmintic for Sheepshould be granted. Submissions should relate only to matters that the

APVMA is required by legislation to take into account in deciding whether to grant the application. These

grounds include occupational health and safety, chemistry and manufacture, residues, safety and first

aid, environmental fate and toxicity, trade and efficacy. Submissions should state the grounds on which

they are based. Comments received outside these grounds cannot be considered by the APVMA.


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vi PUBLIC RELEASE SUMMARY ZOLVIX MONEPANTEL BROAD SPECTRUM ORAL ANTHELMINTIC FORSHEEP

Submissions must be received by the APVMA by close of business on Monday 5 July 2010 and be directedto the contact listed below. All submissions to the APVMA will be acknowledged in writing via email or by

post.

Relevant comments will be taken into account by the APVMA in deciding whether the product should be

registered and in determining appropriate conditions of registration and product labelling.

When making a submission please include:

Contact name

Company or Group name (if relevant)

Postal Address

Email Address (if available)

The date you made the submission.

All personal and confidential commercial information (CCI)1

material contained in submissions will be

treated confidentially.

Written submissions on the APVMAs proposal to grant the application for registration that relate to the

grounds for registration should be addressed in writing to:

Zuzanna Rajczyk

Veterinary Medicines Program

Australian Pesticides and Veterinary Medicines Authority

PO Box 6182

Symonston ACT 2609

Phone: (02) 6210 4733

Fax: (02) 6210 4741

Email: [email protected]

Further information

Further information can be obtained via the contact details provided above.

Further information on public release summaries can be found on the APVMA website:

http://www.apvma.gov.au

1A full definition of "confidential commercial information" is contained in the Agvet Code.
http://www.apvma.gov.au/http://www.apvma.gov.au/


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INTRODUCTION 1

1 INTRODUCTION

The Australian Pesticides and Veterinary Medicines Authority (APVMA) has before it an application from

Novartis Animal Health Australasia Pty Ltd for registration of a new product, Zolvix Monepantel Broad

Spectrum Oral Anthelmintic for Sheep, containing the new active constituent monepantel. This publication

provides a summary of the data assessed and an outline of the regulatory considerations for the proposed

registration of Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep.

Internal parasites are a major problem in sheep in Australia. Anthelmintics are used to control worms in

sheep, however development of resistance to the commonly used anthelmintics is becoming an increasing

problem.

Monepantel is a new amino-acetonitrile derivative (AAD) anthelmintic with a novel mode of action. It acts on

a nematode-specific ACR-23 nicotinic acetylcholine receptor sub-unit.

Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep is an oral drench that contains 25 mg/mL

monepantel.

The proposed use is for the treatment and control of AAD-sensitive strains of gastro-intestinal roundworms

(nematodes), including macrocyclic lactone, benzimidazole (white), levamisole (clear) and morantel-resistant

strains in sheep.

The proposed dose rate is 2.5 mg monepantel/kg bodyweight (1 mL Zolvix/10 kg bodyweight). Zolvix

Monepantel Broad Spectrum Oral Anthelmintic for Sheep is administered as a single treatment. If repeat

treatments are necessary, sheep are not to be retreated less than 21 days after the last treatment and after 3

consecutive treatments, 115 days must elapse before treating again with Zolvix.

Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep will be packaged in 0.25L, 0.5L, 1L, 2.5L, 5L

and 10L containers.

Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep is currently registered in New Zealand,

Uruguay and 27 countries in the European Union.

The APVMA seeks public comment on the product outlined in this document prior to the product being

registered for use in Australia. The APVMA will consider all responses received during the public

consultation period in deciding whether the product should be registered and in determining conditions of

registration and product labelling.


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2 PUBLIC RELEASE SUMMARY ZOLVIX MONEPANTEL BROAD SPECTRUM ORAL ANTHELMINTIC FORSHEEP

2 CHEMISTRY AND MANUFACTURE

2.1 ACTIVE CONSTITUENT

Monepantel is a new active constituent and there is no compendial specification available.

The Pharmaceutical Chemistry Section of the APVMA has evaluated the chemistry aspects of monepantel

(manufacturing process, quality control procedures, batch analysis results and analytical methods).

The chemical active constituent monepantel has the following properties:

COMMON NAME (ISO): Monepantel (INN)

CHEMICAL NAME: N-[(1S)-1-Cyano-2-(5-cyano-2-fluoromethylphenoxy)-1-methylethyl]-4-trifluoromethylsulfanylbenzamide

CHIRALITY: The active substance has one chiral centre and possesses two enantiomers: theactive (S)-enantiomer and the inactive (R)-enantiomer, which is considered an

impurity

PRODUCT NAME: Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep

CAS REGISTRY NUMBER: 887148-69-8

EMPIRICAL FORMULA: C20H13F6N3O2S

MOLECULAR WEIGHT: 473.39

PHYSICAL FORM: Powder

COLOUR: White

OPTICAL ROTATION: -32 ([]580 nm)

MELTING POINT: 142-149 C (form B), 125 C (form A)

DENSITY: 1.468 g/cm3

OCTANOL/PHOSPHATE

BUFFER (PH 7) PARTITION

COEFFICIENT (LOG POW):

4.2-4.7 (@ 20 C)

POLYMORPHISM (FORM B): Orthorhombic

VAPOUR PRESSURE AT 25OC: 2.8 x 10-11 hPa (extrapolated value)

SOLUBILITY Practically insoluble in water (0.08 mg/L), slightly soluble in propylene glycol (6.9g/L) and n-octanol (7.3 g/L), soluble in ethanol (60.7 g/L) and freely soluble in

polyethylene glycol 300 (156.1 g/L) and dichloromethane (175 g/L)


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CHEMISTRY ASSESSMENT 3

STRUCTURAL FORMULA:

O

HN

O

S

CF3

NC

CN

CF3

2.2 PRODUCT

Dose form: Oral drench

Formulation type: Non-aqueous solution

Level of active: 25 mg/mL monepantel

Physical properties Appearance: clear yellow to orange solution

Storage and stability

The applicant provided the results of real time and accelerated stability testing conducted using samples

stored in the proposed commercial containers. The results indicate that the formulated product is expected to

be stable for the duration of the shelf life when stored below 30 C (room temperature) in the proposed

commercial packaging. After initial opening, the product is expected to be stable for 12 months when stored

below 30 C (room temperature) in the proposed commercial packaging.

Packaging

Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep will be packaged in 0.25, 0.5, 1, 2.5, 5 and10 L fluorinated HDPE bottles or laminated aluminium pouches. The integrity of the container materials was

demonstrated in the storage stability studies. The product is not expected to have an adverse effect on the

packaging and the packaging is not expected to have an adverse effect on the product.

2.3 RECOMMENDATION

The Pharmaceutical Chemistry Section of the APVMA has evaluated the chemistry and manufacturing

aspects of the monepantel and is satisfied that all the data requirements (including the physico-chemical

properties, spectral identification, manufacturing and quality control aspects, impurity formation, active

constituent specification, stability, batch analysis data, analytical methods and packaging information)necessary for the approval of this new active constituent have been met.


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The Pharmaceutical Chemistry Section of the APVMA has evaluated the chemistry and manufacturingaspects of Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep and is satisfied that all the data

requirements (including the formulation composition, manufacturing and quality control aspects, product

specification, batch analysis, stability, analytical methods, packaging and label) necessary for the approval of

this new veterinary chemical product have been met.

The Pharmaceutical Chemistry Section of the APVMA is satisfied that the chemistry requirements of

Sections 14(4) and 14(5) Agricultural and Veterinary Chemicals Codes have been met.


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TOXICOLOGY ASSESSMENT 5

3 TOXICOLOGICAL ASSESSMENT

3.1 EVALUATION OF TOXICOLOGY

The Office of Chemical Safety and Environmental Health (OCSEH) within the Department of Health and

Ageing, Australia has conducted the toxicology assessment of monepantel.

The toxicological database for monepantel is quite extensive and consists primarily of toxicity tests

conducted in laboratory animals. In interpreting the data it should be noted that toxicity tests generally use

doses that are high compared with likely human exposures. The use of high doses increases the likelihood

that potentially significant toxic effects will be identified.

Findings of adverse effects in any one species do not necessarily indicate such effects might be generated in

humans. However, from a conservative risk assessment perspective, adverse findings in animal species are

assumed to represent potential effects in humans unless convincing evidence of species specificity is

available. Where possible, considerations of the species-specific mechanisms of adverse reactions weigh

heavily in the extrapolation of animal data to likely human hazard. Equally, consideration of the risks to

human health must take into account the likely human exposure levels compared with those, usually many

times higher, which produce effects in animal studies.

Toxicity tests should also indicate dose levels at which the specific toxic effects are unlikely to occur. Such

dose levels as the No-Observable-Effect-Level (NOEL) are used to develop acceptable limits for dietary orother intakes (ADI and ARfD) at which no adverse health effects in humans would be expected.

Toxicokinetics and Metabolism

Monepantel was only moderately absorbed in rats (up to approximately 50%) after oral administration.

Excretion was mainly via the faeces, with no unchanged monepantel following intravenous administration.

After oral administration, between 52% and 75% monepantel was found unchanged in the faeces. No

unchanged compound was found in the urine of either oral or intravenous treated animals. Tissue distribution

was poor and was restricted to hair follicle, liver, subcutis, white fat, skin and the salivary gland.

Elimination of radiolabelled monepantel occurred almost exclusively by biotransformation, mono

exponentially with a terminal half-life between 40 and 60 hours. The metabolites in plasma were comparable

following intravenous and oral administration. The main metabolite, M2, was attributed to the sulfone

derivative of the parent compound. Additionally, up to seven minor or trace metabolites were detected in

plasma extracts. Similar metabolites were observed after multiple dosing. Bile did not contain any parent

compound. A glucuronide (M6) was the main metabolite in bile, which was easily hydrolysed by -

glucuronidase, yielding M3.

When radiolabelled [14

C] monepantel was formulated as a 2.5% solution and applied topically to rats, the

estimated dermal absorption of monepantel was approximately 6%.


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Acute toxicity studies

Acute toxicity studies demonstrated that monepantel has low acute oral and dermal toxicity in rats (LD50s

both > 2000 mg/kg bw). The compound was not a skin irritant but a slight eye irritant in rabbits. It was not a

skin sensitiser in mice. No information is available on the acute inhalational toxicity of monepantel.

The formulated product, Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep, has low acute oral

and dermal toxicity in rats (LD50sboth > 2000 mg/kg bw). It was a slight skin and eye irritant in rabbits and a

skin sensitiser in mice. No information is available on the acute inhalational toxicity of the formulated product.

Short term and subchronic toxicity studies

Wistar rats (5/sex/dose) were administered monepantel [0, 1000, 4000, 12000 ppm] in the diet ad libitumfor

4 weeks. Clinical signs were limited to superficial skin lesions in one high dose female rat. The liver was

identified as the primary target organ. Clinical biochemistry effects included decreased glucose levels and

increased lipid parameters (triglycerides, phospholipids and cholesterol) in medium and high dose males and

in all monepantel treatment groups in females. Liver weight changes were observed at all doses in female

rats and in the medium and high dose males. Centrilobular hypertrophy lesions were observed in the liver in

both sexes at all test item doses. Diffuse follicular hypertrophy lesions were also observed in the thyroid

gland in males at all test item doses and in medium and high dose females. The severity and incidence of

the lesions were dose dependent. No NOEL could be established due to effects observed at all doses.

Beagle dogs (2/sex/dose) were administered monepantel [0, 5000, 15000, 40000 ppm] for four weeks.

Decreased food consumption and body weight loss were observed at the high dose in males. Increased

alkaline phosphatase levels were observed at all monepantel dose levels in both sexes, although without a

dose response relationship. Dose-related decreases were observed in the absolute and relative thymus

weights in all treated animals of both sexes. Higher adrenal gland weights were recorded in all treated

animals of both sexes. Increased liver weights were observed in females at 5000 and 15000 ppm and

increased thyroid gland and liver weights were recorded in a single female at the 40,000 ppm treatment

level. Microscopic investigation showed minimal to moderate thymus involution in all high dose treated

animals. A NOEL for this 4-week dog study could not be established due to effects including elevated

alkaline phosphatase levels and reduced thymus weights, which were seen at the lowest monepantel dose

level.

SD rats were given monepantel daily in the diet for 90 days at concentrations of 0, 50, 200, 1000 and 12000

ppm. Reduced prothrombin time (PT) was observed at monepantel doses of 1000 ppm and above in both

sexes. Reduced partial thromboplastin time (PTT) and neutrophil count and increased absolute platelet

count were observed in females at the high dose level. Urine pH and the concentrations of Na+, Cl

-,

cholesterol and phospholipids in the blood of female rats were all affected at doses of 1000 ppm and above.

A significant reduction in aspartate aminotransferase (ASAT) levels was observed in female rats at 200 ppm

and 12000 ppm monepantel and the liver of female animals was mostly affected at 1000 ppm and above. At

12000 ppm there were pathologies of the ovary in 3/10 rats. Effects on testes consisted of

hypospermatogenesis in 8/10 males dosed at 12000 ppm. Blood albumin and Na+

concentrations were also

affected when monepantel was given to male rats at 1000 ppm and above. There was a significant reductionin the bilirubin level at doses of 1000 ppm and above. In the 12000 ppm group, this reduction in bilirubin


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TOXICOLOGY ASSESSMENT 7

concentration was not reversed even 4 weeks after monepantel was withdrawn. Overall, the NOEL is 200ppm (14 mg/kg bw/d)

In a 13-week dietary study, male and female beagle dogs were fed monepantel at 0, 300, 3000 or 30000

ppm daily for 90 days. Most treatment-related changes were observed in groups dosed at 3000 ppm

monepantel and above. In the blood, there was reduced activated partial prothrombin time concomitant with

a mild but significant reduction in Ca2+

level at 3000 ppm and above in males and 30000 ppm in females. At

the highest dose, both sexes had increased albumin concentration and albumin/globulin ratio. Male dogs

given 3000 ppm or above had increased total plasma protein concentrations. Alkaline phosphatase (ALP)

was markedly increased in both sexes at 3000 ppm and above. Organs mostly affected by monepantel

administration were the liver, small intestine and pancreas. There were dilated glands of the duodenum and

jejunum in both sexes of dogs as well as an increase in the liver weight of female dogs at 300 ppm and

above. These monepantel-related effects were mostly reversible within 4 weeks of the test item being

withdrawn from the diet. No NOEL could be established given the treatment-related effects in liver and small

intestine seen at the lowest dose studied.

CD-1 mice of both sexes were dosed with monepantel in the diet ad libitumat concentrations of 0, 30, 120,

600 or 6000 ppm for 13 weeks. The liver was the target organ of toxicity. A dose-related increase in total

bilirubin was observed at the two highest doses in males and in females. Cholesterol concentrations were

increased in a dose-related manner in both sexes. An increase in the incidence and severity of hepatic focal

necrosis was seen in females at 600 ppm and above. Treatment-related focal necrosis of the liver was also

seen in males at 6000 ppm. A NOEL of 120 ppm (17.97 mg/kg bw/d) has been established for this study,

based on hepatic focal necrosis (females only at 600 ppm), fatty changes in the liver, and elevated lipid

parameters in both sexes at 600 ppm and above.

Long term toxicity and carcinogenicity studies

In a 52-week chronic oral toxicity study, Wistar rats were dosed with monepantel in the diet ad libitumat

concentrations of 0, 50, 200, 1000 or 12000 ppm. Monepantel-related changes included increased lipid,

protein, albumin and globulin levels and decreased glucose levels in the blood at 12000 ppm. Dose related

increases in the absolute liver weight, the liver to body weight ratio and liver to brain weight ratios were

observed at 1000 ppm and above. The NOEL based on the results of this study for monepantel administered

orally via the diet is 200 ppm (10.67 mg/kg bw).

Beagle dogs were administered monepantel at dietary concentrations of 0, 100, 300 and 3000 ppm for 52

weeks. Treatment-related effects consisted of a decrease in activated partial thromboplastin time in males

and females at 300 ppm and above, an increase in fibrinogen levels in males and an increase in alkaline

phosphatase activity as well as thyroid weight in males and females. Other changes at 300 ppm and above

included changes in liver weight in females (with histopathological changes), an increase in the incidence

and severity of intestinal gland dilation in males and females as well as an increased incidence in brown

pigments in tubular cells of the kidney in males. Therefore, overall, the lowest dose of 100 ppm (equivalent to

2.96 mg/kg bw/d) was established as the NOEL for this study.

In a 78-week oncogenicity study, monepantel was administered ad libitumto CD-1 mice at dietaryconcentrations of 0, 10, 30, 120 and 500 ppm. Mortality rate was slightly increased in females dosed at 500

ppm compared to the control (34% vs 14%). Increases were observed in liver weights at 120 ppm and above


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and spleen weights at 500 ppm, together with findings of fatty liver changes at 120 ppm and above.Monepantel treatment did not reveal a carcinogenic potential. The NOEL for this study is 30 ppm (4.2 mg/kg

bw/d).

In a 104-week oncogenicity (feeding) study, Wistar rats were given monepantel at dietary concentrations of

0, 100, 1000 and 12000 ppm. Reduced body weight was observed at 12000 ppm and increases in the liver,

kidney and heart weights, albeit without microscopic findings, were observed at 1000 ppm and above. Based

on the results of this study, monepantel is not carcinogenic in rats. The NOEL for this study is 100 ppm (4.63

mg/kg bw/d).

Reproduction and Developmental Studies

In a 2-generation reproduction study, rats received 0, 200, 1500 or 12000 ppm of monepantel in the daily

diet prior to pairing, throughout pairing, gestation and lactation for two generations. In the absence of any

reproductive effects up to and including the top dose of 12000 ppm, the NOEL for reproductive toxicity in this

2-generation study is 12000 ppm (647 mg/kg bw/d). For systemic toxicity, a NOEL of 200 ppm (10.5 mg/kg

bw/d) was established based on increased absolute and relative liver weights in conjunction with

hepatocellular hypertrophy, and increases in cortical cell hypertrophy of the adrenal glands at 1500 ppm and

above in P and P1 generation females.

In a developmental study, female rats cohabited with males until copulation was confirmed. The assumed

pregnant rats then received 0, 100, 300 or 1000 mg/kg bw/day of monepantel by gavage from day 6 to day

20 of pregnancy. There were no treatment-related effects in this study. The NOEL in this study for both

maternal and developmental toxicity was 1000 mg/kg bw/day, the highest dose tested. Given that

monepantel exhibited systemic toxicity in other repeat dose studies (i.e. liver toxicity at doses lower than

1000 mg/kg bw/d) and some relevant parameters (organ weights and histopathology, haematology and

clinical chemistry) were not measured in this study, it is considered that the maternal NOEL value observed

in this study has limited value and the true maternal NOEL value could be below 1000 mg/kg bw/d.

In a second developmental study, female rabbits cohabited with males until copulation was confirmed. The

assumed pregnant rabbits received 0, 100, 300 or 1000 mg/kg bw/d of monepantel by gavage from day 6 to

day 27 of pregnancy. Food consumption was sometimes lower than controls in all treated groups without a

dose-relationship but body weight gains were not affected. There were limited findings at 1000 mg/kg bw/d ofan undescribed palate abnormality in a single animal in 2 litters and an observation of the aorta being

duplicated from the bladder to kidneys and unstructured tissue within the nasopharynx in foetuses from a

single litter. These were not considered to provide sufficient evidence that monepantel is hazardous for

developmental toxicity. However, the NOEL for developmental toxicity was 300 mg/kg bw/day based on the

above limited findings, while the NOEL for maternal toxicity was 1000 mg/kg bw/d as no maternal toxicity

was observed in this study.

Genotoxicity Studies

No evidence of a mutagenic potential for monepantel was observed in a battery of in vitroand in vivo

genotoxicity assays that assessed gene mutation and/or chromosome aberration.


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4 RESIDUES ASSESSMENT

4.1 INTRODUCTION

Monepantel is a new anthelmintic, currently not registered for use in any animal species in Australia.

Therefore, Maximum Residue Limits (MRLs) for monepantel in edible sheep tissues need to be established

to cover the proposed product use-pattern. These MRLs have been set using the JECFA MRL-setting

approach (as adopted by the APVMA on 1 July 2006).

4.2 DATA PROVIDEDThe Applicant provided details of metabolism studies that were conducted with monepantel in a range of

animal species, including rats, dogs and sheep. Additionally, details of three tissue residues decline trials

conducted in sheep with the proposed formulation were provided.

4.3 EVALUATION SUMMARY

Metabolism of monepantel

Absorpt ion

Monepantel is well absorbed following oral administration. In rats, following a single oral administration of 10

mg [14

C] monepantel/kg bw, peak mean plasma concentrations of14

C (1.26 0.61 mol/L) were reached 2

hours after treatment, and declined constantly until 96 hours after the treatment, with only trace amounts

remaining in blood and plasma (0.004 mo/L). When sheep were administered a single oral dose of 1.66 mg

or 4.60 mg [14

C] monepantel/kg, peak blood concentrations of monepantel and monepantel sulphone (M2)

were reached at 8 and 24 hours, respectively, after treatment.

Distribution

In rats, following daily administration of [

14

C] monepantel for 7 days, 6 hours after the last treatment, highesttissue residues were found in liver (0.6-2.0 %) and fatty tissue (0.3-2.9 %), followed by adrenal gland,

pancreas and ovaries. The other organs sampled contributed liver>>>muscle>kidney.

Metabolism

The metabolism of monepantel involves: (i) oxidation of monepantel to monepantel sulphoxide (M1),

followed by a rapid oxidation to monepantel sulphone (M2) and a slower oxidation to M3; (ii) cleavage to


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ASSESSMENT OF OVERSEAS TRADE ASPECTS OF RESIDUES IN FOOD 11

produce M4 and its sulphate conjugate (M5); and (iii) hydrolysis to produce an alcohol and an acid, whichare eliminated via the urine.

When sheep were administered a single oral dose of 5 mg [14

C] monepantel/kg bw, monepantel sulphone

was the main metabolite. Monepantel was a minor constituent and was found only at the earlier sampling

times. The decline of monepantel sulphone residues is mirrored by the decline of TRRs in all edible tissues.

Therefore, monepantel sulphone is an appropriate marker residue for liver, kidney, muscle and fat.

Excretion

Monepantel is excreted mainly in the faeces. When sheep were administered a single oral dose of 5 mg [14

C]

monepantel/kg bw, 14 days after treatment, total radioactivity recovered and accounted for was 94-98 %.The radioactivity was excreted mainly through the faeces and bile (53-61 %), and urine (~30 %).

In faeces, the main metabolite was monepantel sulphone, followed by monepantel, especially at the early

sampling times. Urinary metabolites identified were M4 (phenol) and M5 (sulphate).

Comparative metabolism

The pharmacokinetic profiles of the veterinary chemical and its metabolites in the target animal species must

be qualitatively comparable with those of the laboratory animal species used to establish the health

standards, to verify the relevance of the toxicological effects and NO(A)ELs, and thereby validate the dietary

exposure assessments. Based on the available metabolism data, it is concluded that the metabolism ofmonepantel in sheep is qualitatively similar to that determined in laboratory species (dogs and rats).

Summary

Monepantel sulphone was the main metabolite in edible tissues. Monepantel and monepantel sulphone

accounted for most of the TRRs in edible tissues, with other minor metabolites identified having no

toxicological significance. The decline of monepantel sulphone residues is mirrored by the decline of TRRs in

all edible tissues. Therefore, monepantel sulphone is an appropriate marker residue for liver, kidney, muscle

and fat. The relative rank order for monepantel residues in edible tissues is: fat>liver>>>muscle>kidney.

Analytical method

Details were provided for a validated analytical method that could be used to determine monepantel residues

in edible tissues from sheep. The method involves monepantel sulphone being extracted from homogenised

tissue samples with acetonitrile, cleaned up on SPE cartridges, and analysed using an HPLC method

coupled with UV detection. The concentration of monepantel sulphone is determined using a standard

calibration curve of peak response to external standard concentration.

The Limits of Quantification (LOQs) and Limits of Detection (LODs) for the analytical method are tabulated

below.


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Table 1: The Limits of Quantification (LOQs) and Limits of Detection (LODs) for the analytical method

TISSUE MATRIX LOQ (g/kg) LOD (g/kg)Liver 10 3.6

Muscle 10 4.5

Kidney 10 4.7

Fat 10 6.3

Residue definition

Monepantel sulphone is an appropriate marker residue for monepantel, as the sulphone metabolite

represents a large and relatively constant fraction of total residues in all edible tissues. Therefore, the

residue definition for monepantel is monepantel sulphone.

The ratio of marker residue to total residues is 0.94 for muscle, and 0.68 for fat, liver and kidney.

Residues Trials

Three tissue residues trials were conducted with Zolvix Monepantel Broad Spectrum Oral Anthelmintic for

Sheep. In each trial, sheep (n=32-48) were administered a single oral drench of 3.75 mg monepantel/kg bw

(ie 1 maximum label dose rate). Groups of animals (n=8) were sacrificed at specified times ranging from 7

to 127 days after treatment. Samples of liver, kidney, muscle, subcutaneous fat and peri-renal fat were

collected and analysed for their concentrations of monepantel residues. The residues results from these

three trials are combined and presented graphically below.


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Monepantel sulphone (AHC 2144670) residues in all edible tissues from sheep that were administereda single oral treatment at the maximum proposed label rate

Figure 1: AHC 2144670 residues in peri-renal fat fromsheep administered a single oral dose of 3.75 mg

AHC 2102225/kg bw (1 maximum dose rate)

Days after treatment

0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126

A

HC-2144670residues(g/kg)

0

1000

2000

3000

4000

5000

6000

7000

Proposed MRL (7000 g/kg)

Figure 2: AHC 2144670 residues in subcutaneous fat fromsheep administered a single oral dose of 3.75 mg



0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 1 05 112 119 126

A

HC-2144670residues(g/kg)

0

1000

2000

3000

4000

5000

6000

7000


Figure 3: AHC 2144670 residues in muscle from sheepadministered a single oral dose of 3.75 mg



0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126

AH

C-2144670residues(g/kg)

0

100

200

300

400

500

600

700

800


Figure 4: AHC 2144670 residues in kidney from sheepadministered a single oral dose of 3.75 mg



0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126

AH


0

500

1000

1500

2000


Figure 5: AHC 2144670 residues in liver from sheepadministered a single oral dose of 3.75 mg



0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126

AH


-500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500


Highest monepantel sulphone residues occured in fat and liver. Consequently, it is the decline of monepantel

sulphone residues in sheep fat and liver (the target tissues) that determines the length of the domestic

withholding period (WHP), the re-treatment interval, and the Export Slaughter Interval (ESI) for the use of the

new product in sheep.

MRL recommendat ions

The following monepantel MRLs are recommended to cover the occurrence of monepantel residues in ediblesheep tissues after the 14 day WHP has been observed: sheep muscle - 0.7 mg/kg; sheep fat - 7 mg/kg;

sheep liver - 5 mg/kg; sheep kidney - 2 mg/kg.


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Wit hholding period - Meat

Statistical analysis of the residues data indicates that monepantel residues in all edible sheep tissues will

have declined to below the relevant recommended monepantel MRLs at 14 days after treatment. Therefore,

a 14 day meat WHP is recommended for the use of Zolvix Monepantel Broad Spectrum Oral Anthelmintic for

Sheep.

Withholding period - Milk

In the absence of any milk residues data, the following milk WHP is recommended:

DO NOT USEin female sheep which are producing or may in the future produce milk or milk products forhuman consumption.

Re-treatment interval

The Applicant conducted a residues trial where sheep were administered 3.75 mg monepantel/kg bw (ie 1

maximum label dose rate) at 21 day intervals. Groups of animals were sacrificed at 21 days after the second,

third and fourth treatment, as well as 14 days after the fourth treatment. Samples of liver and peri-renal fat

were collected and analysed for their concentrations of monepantel residues. Statistical analyses comparing

monepantel sulphone residues in peri-renal fat and liver of sheep following a single oral dose and 4

consecutive treatments 21 days apart indicate that there is no significant difference between monepantel

sulphone residues in tissues following a single oral dose and 4 consecutive treatments 21 days apart.However, the residues data show a decline in monepantel sulphone residues at 21 days after the 2

ndand 3

rd

treatments, but not after the 4th

treatment. Therefore, a minimum re-treatment interval of 21 days is

supported, with a maximum of three treatments. After the third treatment, a period of 115 days (i.e. the time

taken for monepantel residues to decline to LOQ) must be observed before further treatment.

Fat solubility and potential for bioaccumulation

The report of the Thirty-eighth Session of the Codex Committee on Pesticide Residues (April 2006) revisited

the issue of fat-soluble pesticides in meat and fat. The meeting decided to revise the empirical limits

recommended by the 1991 JMPR when considering log Pow, so that when no evidence is available to the

contrary and log Pow exceeds 3, the compound would be designated fat-soluble, and when log Pow is less

than 3 it would not be so designated.

The octanol/phosphate buffer partition coefficient (log Pow) for monepantel is 4.2-4.7. Accordingly,

monepantel is considered fat-soluble. However, it is concluded that the potential for monepantel to

bioaccumulate is low, as the results from residues trials demonstrate that residues of monepantel do not

accumulate in either fat or liver of treated sheep.


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Dietary risk assessment

Chronic dietary exposure assessment

The chronic dietary exposure to monepantel residues is estimated by the National Estimated Daily Intake

(NEDI) calculation encompassing all registered/temporary uses of the chemical and the mean daily dietary

consumption data derived from the 1995 National Nutrition Survey of Australia. The NEDI calculation is

made in accordance with WHO Guidelines and is a conservative estimate of dietary exposure to chemical

residues in food. The NEDI for monepantel is equivalent to 3.14% of the ADI. It is concluded that the chronic

dietary exposure to monepantel is acceptable.

Acute dietary exposure assessment

The acute dietary exposure is estimated by the National Estimated Short Term Intake (NESTI) calculation.

The NESTI calculations are made in accordance with the deterministic method used by the JMPR with

97.5th percentile food consumption data derived from the 1995 National Nutrition Survey of Australia. NESTI

calculations are conservative estimates of acute exposure (24 hour period) to chemical residues in food. To

date, the Office of Chemical Safety and Environmental Health (OCSEH) has not established an Acute

Reference Dose (ARfD) for monepantel. Therefore, no estimate of the acute dietary exposure to monepantel

has been performed.

4.4 CONCLUSIONS AND RECOMMENDATIONS

Registration of the product

The Veterinary Residues Team (VRT) has evaluated the residues aspects of Zolvix Monepantel Broad

Spectrum Oral Anthelmintic for Sheep. The VRT has considered the available metabolism, residue trials,

analytical methodology, fate in storage, processing data and residues in trade issues, including that

submitted by Novartis Animal Health Australasia Pty Limited to support their application to register a new oral

product for use in sheep.

The VRT recommends that the APVMA be satisfied that the use of the product in accordance with the

required label instructions would not be harmful or an undue hazard to the safety of people exposed to

residues in food as per section 14(3)(e)(i) & (ii) and that the residues aspects of section 14(5) of the Agvet

Codes have been met.

The VRT supports the following label instructions for Zolvix Monepantel Broad Spectrum Oral Anthelmintic

for Sheep:

ANIMAL PURPOSE DOSE RATE

Sheep For the treatment and

control of intestinal

nematodes.

Nominal: 1 mL product/10 kg bw (i.e. 2.5 mg monepantel/kg bw)

Maximal: 1.5 mL product/10 kg lamb (i.e. 3.75 mg monepantel/kg bw)


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Restraints:

DO NOT USE in female sheep which are producing or may in the future produce milk or milk products for

human consumption.

Retreatment interval:

DO NOT re-treat less than 21 days after the last treatment. After three consecutive treatments, 115 days must

elapse before treating again with Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep.

Withholding Periods:

MEAT: DO NOT USE less than 14 days before slaughter for human consumption.

MILK: DO NOT USE in female sheep which are producing or may in the future produce milk or milk products for

human consumption.

Trade Advice:

EXPORT SLAUGHTER INTERVAL (ESI): DO NOT slaughter for export less than 115 days after treatment.

Recommended amendments to the MRL standard

The following amendments to the MRL Standardare recommended:

Table 2: MRL Standard - Table 1 Amendments

Table 1

COMPOUND FOOD MRL (mg/kg)

ADD:

MONEPANTEL MM 0822 Sheep muscle 0.7

MF 0822 Sheep fat 7

MO 1288 Sheep kidney 2

MO 1289 Sheep liver 5

Table 3: MRL Standard Table 3 Amendments

Table 3

COMPOUND RESIDUE

ADD:

Monepantel Monepantel sulphone


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5 ASSESSMENT OF OVERSEAS TRADE ASPECTS OF RESIDUESIN FOOD

Commodities exported

Australian exports of mutton/lamb and live sheep could be affected by the use of Zolvix Monepantel Broad

Spectrum Oral Anthelmintic for Sheep.

Destination of Exports

Consultation within Commonwealth and State Government agencies and with the Sheepmeat Council ofAustralia has determined that the APVMA will consider the standards of China, Commonwealth of

Independent States (CIS), European Union (regarded as 27 countries as of January 2007), Japan, Saudi

Arabia, United Arab Emirates (UAE) and USA, along with the Maximum Residue Limit Standard of the Codex

Alimentarius Commission, when determining Export Slaughter Intervals.

Overseas registration and approved label instructions

Novartis Animal Health Australasia Pty Ltd has indicated that Zolvix Monepantel Broad Spectrum Oral

Anthelmintic for Sheep is registered in the European Union, New Zealand and Uruguay.

Comparison of Australian MRLs with Codex and overseas MRLs

The Codex Alimentarius Commission (Codex) is responsible for establishing Codex Maximum Residue

Limits for pesticides and veterinary medicines. Codex Maximum Residue Limits are primarily intended to

facilitate international trade and accommodate differences in Good Agricultural Practice (GAP) employed by

various countries. Some countries may accept Codex Maximum Residue Limits when importing foods.

Monepantel has not been considered by Codex and MRLs have only been established in the European

Union and New Zealand. Comparisons of the recommended Australian and overseas residues definitions

and MRLs/tolerances for monepantel are tabulated below.


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Table 4: Comparison of the recommended Australian and overseas monepantel MRLs/tolerances

OVERSEAS MRLs/TOLERANCE (mg/kg)COMMODITY

Codex EuropeanUnion

USA China Japan CIS1 SaudiArabia

UAE2

RECOMMENDEDAUSTRALIAN MRL

(mg/kg)

Sheep muscle -- 0.7 -- -- -- -- -- -- 0.7

Sheep fat -- 7.0 -- -- -- -- -- -- 7.0

Sheep liver -- 5.0 -- -- -- -- -- -- 5.0

Sheep kidney -- 2.0 -- -- -- -- -- -- 2.0

1Commonwealth of Independent States (CIS)

2United Arab Emirates (UAE)

Potential risk to trade

Export of treated produce containing finite (measurable) residues of monepantel may pose a risk to

Australian trade in situations where (i) no residue tolerance (import tolerance) is established in the importing

country, or (ii) where residues in Australian produce are likely to exceed a residue tolerance (import

tolerance) established in the importing country.

Currently, the European Union is the only country amongst those considered by the APVMA when

determining ESIs, with monepantel MRLs for sheep muscle, fat, liver and kidney (0.7 mg/kg, 7.0 mg/kg, 5.0

mg/kg and 2.0 mg/kg, respectively) and these MRLs are equivalent to the recommended Australian

monepantel MRLs. China, CIS, Japan, Saudi Arabia, UAE, USA and Codex do not have MRLs/tolerances for

monepantel in sheep commodities. Therefore, these are considered to be the most sensitive export markets

for Australian sheep commodities containing monepantel.

Identi f icat ion of t he appropri ate ESI endpoint

In the absence of importing standards for monepantel residues in edible tissues in China, CIS, Japan, Saudi

Arabia, UAE, USA and Codex, it is concluded that the appropriate endpoint for determination of the ESI for

Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep is the LOQ of the validated analytical

method (i.e. 0.01 mg/kg).

Estimat ion of t he ESI

Statistical analysis (using the EMA Meat Program) of the residues data indicates that monepantel residues in

fat, liver, kidney and muscle from treated sheep are likely to be below 0.01 mg/kg at 115 days after

treatment. Therefore, an ESI of 115 days has been recommended for the use of Zolvix Monepantel Broad

Spectrum Oral Anthelmintic for Sheep.


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Conclusion

Overall, the risk to Australias export trade in sheep commodities is considered to be low when the

recommended ESI of 115 days is observed for Zolvix Monepantel Broad Spectrum Oral Anthelmintic for

Sheep.

The Veterinary Residues Team (VRT) recommends that the APVMA be satisfied that the use of the product

in accordance with the required instructions would not unduly prejudice trade and commerce between

Australia and places outside Australia as per section 14(3)(e)(iv) of the Agvet Codes, as monepantel

sulphone residues in edible tissues from sheep are expected to have declined to levels below the standards

applied by the importing countries when the recommended ESI of 115 days is observed.


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6 OCCUPATIONAL HEALTH AND SAFETY ASSESSMENT

6.1 HEALTH HAZARDS

Monepantel has low acute oral and dermal toxicity in rats. It is not a skin irritant but a slight eye irritant in

rabbits. It was not a skin sensitiser in mice. No information is available on its acute inhalational toxicity.

Monepantel is not listed on the Australian Safety and Compensation Council (ASCC) Hazardous Substances

Information System (HSIS) Database(ASCC, 2005)

The formulated product, Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep, has low acute oral

and dermal toxicity in rats. It was a slight skin and eye irritant in rabbits and a skin sensitiser in mice. Noinformation is available on its acute inhalational toxicity. Based on the product toxicology information and

concentrations of monepantel and other ingredients in the product, the product is classified as a hazardous

substance in accordance with NOHSC Approved Criteria for Classifying Hazardous Substances (NOHSC,

2004) with the following risk phrases:

R43 May cause sensitisation by skin contact

R38 Irritating to skin

6.2 FORMULATION, PACKAGING, TRANSPORT, STORAGE ANDRETAILING

Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep will be available as a liquid in high-density

polyethylene (HDPE) bottles with induction heat-sealed caps and/or laminated aluminium pouches in the

following pack sizes: 250mL, 500mL, 1L, 2.5L, 5L and 10L. Transport workers and store persons who handle

the packaged products could only become contaminated if packaging was breached.

6.3 USE PATTERN

Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep is a new anthelmintic that is active againsteconomically important nematodes in sheep, including strains resistant to other classes of anthelmintics. The

product will be available at a concentration of 25 mg monepantel /mL and will be administered undiluted by

oral drenching.

6.4 EXPOSURE DURING USE

Farmers and their employees will be the main users of the product. Workers may be exposed to the product

when opening containers, administering the product (or connecting containers to a drenching gun, using the

drenching gun), and cleaning up spills and equipment. Hand contamination is also possible if the animals

cough during administration, when refilling the backpack, if the drenching gun becomes blocked or whencleaning equipment. The potential for exposure during administration of Zolvix Monepantel Broad Spectrum


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OCCUPATIONAL HEALTH AND SAFETY ASSESSMENT 21

Oral Anthelmintic for Sheep is largely via the dermal route. A user guide video at the Novartis Zolvix website: http://www.zolvix.com/optimum/using/shtmlprovides more information on the drenching procedure.

There was no worker exposure study provided for monepantel or the product. Instead, two approaches to

enable an operator exposure assessment were constructed.

These estimations, in conjunction with the toxicology data, showed that for Zolvix Monepantel Broad

Spectrum Oral Anthelmintic for Sheep, the use of elbow length chemical resistant gloves is required to

protect workers.

6.5 EXPOSURE DURING RE-ENTRYAs the product is administered directly into the animals mouth, exposure is not expected to occur during re-

handing of animals. Therefore, there is no risk associated with re-handling animals treated with this product.

6.6 RECOMMENDATIONS FOR SAFE USE

Users should follow the First Aid Instructions and Safety Directions on the product label.

FIRST AID INSTRUCTIONS

If poisoning occurs, contact a doctor or Poisons Information Centre. Phone Australia 131126.

SAFETY DIRECTIONS

May irritate the eyes. Will irritate the skin. Repeated exposure may cause allergic disorders. Avoid contact

with eyes and skin. If product on skin, immediately wash area with soap and water. When using the product

wear elbow length chemical resistant gloves. Wash hands after use. After each days use wash gloves and

contaminated clothing.

6.7 CONCLUSION

Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep can be used safely if handled in accordance

with the instructions on the product label and any other control measures described above. Additional

information is available in the product MSDS.

OCSEH recommends that the APVMA can be satisfied that the proposed use of Zolvix Monepantel Broad

Spectrum Oral Anthelmintic for Sheep would not be likely to have an effect that is harmful to human beings

when used in accordance with label instructions.
http://www.zolvix.com/optimum/using/shtmlhttp://www.zolvix.com/optimum/using/shtml


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7 ENVIRONMENTAL ASSESSMENT

7.1 INTRODUCTION

Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep contains the new active constituent (ac)

monepantel at 25 mg ac/mL and will be administered orally as a drench at a maximum dose of 3.75 mg

ac/kg body weight. It is expected that young animals could receive several treatments during their first year

of life while older animals will receive only a single annual dose. Environmental exposure is expected to

primarily involve excreta in pastures, with aquatic exposure also possible through run-off.

7.2 ENVIRONMENTAL CHEMISTRY AND FATE

Hydrolysis

Based on its chemical structure, monepantel is expected to be stable to hydrolysis under environmental

conditions but may hydrolyse under severe conditions.

Photodegradation

Monepantel is not expected to be readily photodegradable based on its UV-visible absorption spectrum.

Biodegradation

Aerobic soi l met abolism

An aerobic metabolism of [14

C]-monepantel in 3 different soil types treated at a rate of 0.3 mg ac/kg soil

indicated that monepantel has half-lives between 38 and 146 days: the lower the fraction of sand in the soil,

the faster the degradation of monepantel. At the end of the studies, the total recovery (mass balance) was 75

86% of the initial. Most of the applied radioactivity in all 3 soils was extractable. Less than 1% of the total

applied radioactivity was measured in the volatile degradation products (including carbon dioxide). The

amounts of radioactivity extracted from the soil samples decreased over the test duration while the amounts

of non-extractable residues in the soil increased during the course of the experiment.

Metabolism in animals

The pharmacokinetics, metabolism, distribution and excretion of monepantel have been evaluated in rats.

Uptake and elimination are rapid and a substantial portion of the parent compound is excreted metabolised.

After repeated oral administration for 7 days, the major proportion (60-80%) of the applied radioactivity was

recovered in faeces and 3-6% in urine. In the faeces, the parent represented 25% of the mean daily dose

and the metabolites >52%.

A study was conducted to investigate the absorption, distribution, metabolism and excretory patterns ofmonepantel in sheep at oral dose rates of 1.7 and 4.6 mg ac/kg bw. The amount of radioactivity recovered

was 109-114%. Within 12 days, 87-92% were eliminated. At the time of slaughter, 17-27% remained in the


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ENVIRONMENTAL ASSESSMENT 23

animal and was found mostly in fat (11-21%) and muscle (4%). Pharmacokinetics in blood as well asresidues in faeces and tissuewere dominated by the active sulfone metabolite AHC 2144670 and to a much

lesser extent the parent compound. In urine,no parent compound or sulfone was detected, whereas two

prominent urinary metabolites were discovered: AHC 2166636 and AHC 2166637.

Another study was conducted to investigate the residue depletion as well as absorption, distribution,

metabolism and excretion of [14

C]-AHC 2102225 (monepantel) after a single oral administration to sheep at a

dose rate of 5 mg ac/kg bw. The mean recovery of radioactivity from urine was about 30%, faeces 53-61%

and cage wash 1.8-4.2% of the administered dose. Peak mean Total Radioactive Residue (TRR)

concentrations in urine and faeces were observed between 24 and 72 h post dose and decreased steadily

thereafter. The highest overall mean TRR concentration was observed in urine and faeces at 48 h. Most of

the radioactivity was excreted within two weeks, with the faecal pathway being the prominent one. Faecal

metabolites were structurally close to the parent compound, whereas urinary metabolites corresponded to

the products as a result of the cleavage via the ether linkage of the parent.

Mobility

Soil adsorpt ion/desorpt ion st udies

Adsorption/desorption of radiolabelled monepantel was determined in 5 different soil types (sand, two lots of

loamy sand with varying amounts of organic content, clayey loam and loam). A quantitative balance of

radioactivity was established. The adsorption constants (Kd) in the five test soils ranged from 81 to 295 mL/gand the corresponding adsorption coefficient (Koc) values were 6082 to 8880 mL/g. Based on McCalls

Mobility Classifications, monepantel is considered to be immobile in these 5 soils. Desorption of monepantel

from the five different soil types was recalculated at up to 20% of the amount adsorbed. The adsorption

process is considered not to be reversible.

Bioaccumulat ion i n aquat ic organisms

Bioaccumulation studies were not undertaken. Based on the determined value of log Kow 4.2-4.7, it is likely

that monepantel has the potential for bioaccumulation in aquatic organisms. However, it is metabolised in

sheep and release to the aquatic compartment will be low.

7.3 ENVIRONMENTAL EFFECTS

Aquatic organisms

Monepantel is considered to be non-toxic to aquatic organisms (fish, aquatic invertebrates, algae) up to its

limit of water solubility. These were based on Water Accommodated Fraction (WAF) tests at 100 mg WAF/L,

with measured values ranging from 0.1-2 mg ac/L.


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Non-target Invertebrates (Terrestrial)

Eart hworms

The NOEC for mortality, growth, reproduction and feeding activity of the earthworm was 2.4 mg ac/kg dry soil

for an exposure period of 56 days.

Dung Flies

The test item had no effect on hatching rate of flies and development time at 1000 mg ac/kg dry dung. The

NOEC for development of the fly Scathophaga stercorariafrom eggs to adults is 1000 mg ac/kg dung,

indicative of a non-toxic effect.

Arthropods

No test for toxicity to dung beetle larvae was performed but at concentrations of up to 640 mg ac/L,

monepantel had no activity against any of the arthropods such as cat flea, blowfly, chicken red mite, adult

dog tick and domestic fly. In addition, the main metabolites of sulfoxide and sulfone found in treated animals

were determined to be inactive against these arthropods. Based on the available information monepantel

has low activity to a range of arthropods.

Soil Microorganisms

Monepantel did not have an impact on soil microflora, based on the respiratory activity and the soil nitrogen

transformation at a concentration of up to 0.3 mg ac/kg dry soil. It is concluded that the active constituent

does not have a long-term influence on soil microflora.

Phytotoxicity

Monepantel did not show any effects on seedling emergence and seedling growth for oilseed rape, soybean

and oat. The germination rate was not statistically significantly reduced for all species tested. Neither

mortality nor phytotoxic effects were observed for all plants species tested. It is concluded that monepantel

has no significant adverse effect on germination and growth of non-target plants at a concentration of 100

mg ac/kg dry soil.

7.4 PREDICTION OF ENVIRONMENTAL RISK

Aquat ic organisms

DEWHAs environmental risk calculations in the aquatic compartment are based on a worst-case pasture

scenario with direct excretion into surface water by grazing sheep and a worst-case run-off in a feedlot

situation under Australian farm practices for sheep.

Given the acute toxicity of the aquatic organisms was determined to be non-toxic up to its limit of water

solubility of 0.1 mg ac/L and a PECsurface water of 0.4 g/L, the resultant risk quotient indicates an acceptable


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ENVIRONMENTAL ASSESSMENT 25

environmental risk to the aquatic organisms from direct discharge of a fraction of the excreta into a slowflowing stream under a pasture scenario.

A 5% run-off as a result of rainfall into a pond in a feedlot scenario results in a concentration of 4.2 g ac/L

contained in a pond. The risk quotient calculation indicates an unacceptable environmental risk is unlikely to

occur in the aquatic compartment as a result of run-off.

Residual quantities of monepantel are not expected to leach from decaying sheep faeces as a result of

rainfall because of the active constituents low water solubility and its strong association with soil and organic

matter. The decay of sheep faeces contaminated with monepantel on grazing land or in a feedlot is therefore

not expected to constitute an environmental risk to aquatic invertebrates.

Non-target invertebrates and micro-organisms

The PEC in the terrestrial compartment under Australian farm practices was estimated to be 1.7 and 150 g

ac/kg dry soilin pastures and feedlots, respectively,based on 100% of the excreted drug as parent

compound.

The proposed registration of Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep under

Australian farm practices is not expected to present unacceptable risks to arthropods, dung flies and

earthworms, or to have lasting effects on soil respiration and nitrification processes. This is based on studies

showing that the calculated PECs are well below the toxicological end points tested, which showed no

adverse effects.

Non-target vegetation

Monepantel has no significant adverse effect on germination of non-target plants at a concentration of 100

mg ac/kg dry soil. At the soil concentration of 1.7 g ac/kg dry soil, it is clear that there is unlikely to be an

environmental effect on non-target vegetation in pastures.

7.5 CONCLUSION

Given the low toxicity of monepantel to aquatic organisms and its expected low concentration in water, the

environmental risk as a result of discharge to water in a pasture environment and from run-off in a feedlot

scenario is considered acceptable.

On the basis of the low concentration of the active constituent present in treated soils based on the proposed

use pattern and the low toxicity to arthropods, dung flies, micro-organisms and vegetation, there is unlikely to

be an environmental risk to terrestrial organisms in pastures or feedlots.

In order to be satisfied that the proposed uses of Zolvix Monepantel Broad Spectrum Oral Anthelmintic for

Sheep will not lead to an unintended effect that is harmful to animals, plants or the environment at the

proposed rate and following good agricultural practice, DEWHA recommends the following disposal

statement for pack sizes greater than 1L (HDPE or aluminium packaging):


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Triple rinse containers before disposal. Dispose of rinsate or any undiluted chemical according toState/Territory legislative requirements. If not recycling, break, crush or puncture and deliver empty

packaging to an approved waste management facility. DO NOT burn empty containers or product.

For pack sizes 1L or less (HDPE or aluminium packaging), the following disposal statement is

recommended:

Dispose of empty container by wrapping with paper and putting in garbage.

Acceptance of this recommendation allows DEWHA to recommend that the APVMA be satisfied that the

proposed use of Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep would not be likely to have

an unintended effect that is harmful to animals, plants, or things or to the environment.


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EFFICACY AND SAFETY ASSESSMENT 27

8 EFFICACY AND SAFETY ASSESSMENT

Monepantel is a new amino-acetonitrile derivative (AAD) anthelmintic with a novel mode of action. It acts on

a nematode-specific ACR-23 nicotinic acetylcholine receptor sub-unit.

The proposed claims are for the treatment and control of AAD-sensitive strains of gastro-intestinal

roundworms (nematodes), including those macrocyclic lactone, benzimidazole (white), levamisole (clear) and

morantel-resistant strains.

Zolvix will be administered at 2.5 mg monepantel/kg bodyweight (1 mL Zolvix/10 kg bodyweight).

8.1 EVALUATION OF EFFICACY DATA

The efficacy data included a range of parasites in both artificial and natural infection pen studies and field

situations. The studies were well monitored and the analysis was compliant with both WAAVP and APVMA

guidelines.

The pen studies included:

Fourth Stage Larval (L4) Nematodes:

Three Dose Determination Studies (including two conducted in Australia)

Two Formulation Bridging Studies (including one conducted in Australia)

Nine Dose Confirmation Studies (5 conducted in Australia, 3 in Europe and one in New Zealand)

Adult Stage Nematodes

Three Dose Determination Studies (including two conducted in Australia)

One Formulation Bridging Study (conducted in Australia)

Nine Dose Confirmation Studies (6 in Australia and 3 in Europe).

The field studies included two multi-centre field efficacy studies (one each in Australia and New Zealand).

AUSTRALIA NEW ZEALAND EUROPETYPE OF STUDY

L4 Adult L4 Adult L4 Adult

Dose determination 2 2 -- -- 1 1

Formulation bridging 1 1 -- -- -- 1

Dose confirmation 5 6 1 -- 3 3

Field efficacy 1 (12 sites) 1 (18 sites) --


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The dose determination studies tested three doses of monepantel at 1.25, 2.5 and 5.0 mg/kg bw against arange of larval and adult stages of nematodes. Untreated animals served as controls. Sheep were artificially

infected with third stage larvae prior to treatment. In some trials, sheep were infected with known resistant

strains (benzimidazole, levamisole and benzimidazole+levamisole). Total worm counts were conducted 2

weeks (Australia) or 3 weeks (Europe) after treatment. Efficacy against most parasites and stages was

generally >95% at 5.0 and 2.5 mg/kg, consequently a dose of 2.5 mg/kg was selected for the dose

confirmation studies.

The bridging studies were conducted to demonstrate the continuity of data between the near final and final

oral formulations of monepantel. The results indicated that there was no significant difference between the

efficacies of the two formulations.

The dose confirmation studies investigated the efficacy of monepantel at 2.5 mg/kg bw against a range of

larval and adult stages of nematodes. Untreated animals served as controls. Sheep were artificially or

naturally infected with nematodes prior to treatment. In some trials, sheep were infected with known resistant

strains (benzimidazole, levamisole and benzimidazole+levamisole). Faecal egg counts were conducted 1-2

weeks after treatment (2 weeks in Australia/New Zealand). Total worm counts were conducted 1.5-3 weeks

after treatment (2 weeks in Australia/New Zealand). Efficacy against most parasites and stages was

generally >95%.

The field studies investigated the efficacy of monepantel at 2.5 mg/kg bw against natural infections of

gastrointestinal nematodes in sheep grazing pasture. In addition to a negative control group, a range of

positive control groups was also included, with products representing the macrocyclic lactone, benzimidazole

and imidazothiazole classes. Faecal egg counts were conducted 1, 2 and 3 weeks after treatment. Efficacy

against the parasite populations was >95%. The parasite populations included macrocyclic lactone,

benzimidazole, levamisole and benzimidazole+levamisole resistant strains.

The efficacy studies demonstrated that Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep is

effective (>95%) against a range of adult and immature fourth larval stages of gastro-intestinal nematodes of

sheep.

Claims for the following nematode species and stages are supported, when the product is used at the

proposed label dose rate of 1 mL Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep/10 kg

bodyweight:

Haemonchus contortus(adult and immature L4)

Teladorsagia (Ostertagia) circumcincta(adult and immature L4)

Teladorsagia (Ostertagia) trifurcata(adult and immature L4)

Teladorsagia (Ostertagia) davtiani(adult and immature L4)

Trichostrongylus colubriformis(adult and immature L4)

Trichostrongylus vitrinus(adult and immature L4)


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Trichostrongylus rugatus(adult and immature L4)

Trichostrongylus axei(adult and immature L4)

Nematodirus filicollis(adult and immature L4)

Nematodirus spathiger(adult)

Cooperia curticei(adult and immature L4)

Cooperia oncophora(adult and immature L4)

Chabertia ovina(adult and immature L4)

Oesophagostomum venulosum(immature L4)

The claims of efficacy against macrocyclic lactone, benzimidazole, levamisole and morantel resistant strains

of gastrointestinal nematodes are also supported.

No adverse events due to systemic activity of monepantel were reported in any of the studies.

8.2 EVALUATION OF TARGET ANIMAL SAFETY DATA

The applicant provided a comprehensive set of target animal safety studies. This included:

Two Preliminary Studies

Two pivotal studies at 1x, 3x, 5x (repeat dose) and 10x (single dose) maximum label dose

One repeat dose reproductive safety study at 3x maximum label dose in ewes and rams.

The pivotal and reproductive studies were conducted to Good Laboratory Practice. Except for the first

preliminary study, the target animal safety studies were conducted with the final formulation.

In the first preliminary study, adult Suffolk ewes (11 months old) received 50 and 75 mg monepantel/kg bworally and then two weeks later, another 100 and 125 mg/kg. At 100 mg/kg, only a slightly decreased

haemoglobin concentration was apparent. Likely treatment-related changes at 125 mg/kg included a

transient decrease of appetite, increases in fluoride oxalate glucose, serum glucose and urea

concentrations, increased alanine aminotransferase concentrations and decreased haemoglobin

concentrations. The maximum dose tested equated to 33x the maximum label dose of 3.75 mg/kg. Sheep

tolerated the single dose levels well, without toxicologically significant changes in the observed parameters.

In a second preliminary study, 2-3 week old Suffolk lambs weighing 9-11 kg were administered a single dose

of 2 mL product/kg bw (50 mg monepantel/kg bw; 13x maximum label dose). Untreated lambs served as

controls. Immediately after treatment all lambs demonstrated signs of depression. One fatality occurred due

to aspiration during treatment. No other gross or histopathological abnormalities were observed. Apart fromthe single fatality, the dose was clinically well tolerated.


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One pivotal study investigated the safety of a single dose of 37.5 mg monepantel/kg bw (10x maximum labeldose) in 2-4 week old Merino and Suffolk lambs weighing 7-14 kg. Control animals were dosed with saline.

Variable signs of depression were observed in most lambs immediately after treatment. Increased respiratory

rates were seen in three lambs treated with monepantel. Three lambs died within 48 h after treatment due to

aspiration pneumonia and the pathological evidence supported this conclusion. The pathological assessment

indicated that several surviving lambs aspirated small volumes of fluid during treatment. No significant

treatment-related macroscopic or microscopic changes were found in the surviving animals. No

toxicologically meaningful differences in haematological, coagulation or clinical chemistry variables were

found. The lambs grew at normal rates and there were no differences in bodyweight between control and

treatment groups. No specific treatment-related adverse effects were identified and no differences in

response to treatment were noted between Merino and Suffolk lambs.

The second pivotal study investigated the repeat dose safety of the product in 12-15 week old Merino lambs

treated at 1x, 3x and 5x the maximum label dose rate (3.75 mg/kg bw). Control animals were dosed with

saline. The study commenced shortly after lambs were weaned. No treatment-related adverse events were

reported. There was no difference in feed consumption and water consumption between the treated and

control groups. There was no difference between the body weights of treated and control animals at any time

point. There were no relevant differences in the organ weight, the organ weight/body weight and the organ

weight/brain weight ratios at necropsy in any group. No specific treatment-related adverse effects were

identified and no differences in response to treatment were noted. Repeated oral administration of the

formulation at 1x, 3x and 5x the maximum label dose was well tolerated in young, growing Merino lambs.

A repeat dose reproductive safety study was conducted at 3x the maximum label dose. The product was

administered orally at 11.25 mg monepantel/kg bw at repeated intervals throughout an entire spermatogenic

cycle and mating for Merino rams and throughout the follicular phase of reproduction, the gestational period

and after parturition until weaning to Merino ewes to identify potential adverse effects on male and female

fertility and reproductive performance and on offspring viability. Control animals were dosed with saline. The

trial was designed to investigate ram-specific treatment effects, ewe-specific treatment effects and potential

combinatory effects of treatment of both sexes. A series of reproductive parameters were assessed and in

addition, necropsy and gross pathological examination were conducted on a subset of animals. No

significant differences were detected between treated and control animals in reproductive parameters. No

significant macroscopic changes were found at necropsy in the treated animals compared to the control

animals.

The safety studies demonstrate that the margin of safety is satisfactory to support safe administration at the

label dose (of 2.5mg monepantel/kg bw and up to the maximum recommended dose per weight range of

3.75 mg monepantel/kg bw) and frequency in male and female lambs from two weeks of age weighing at

least 10 kg and in breeding animals of both sexes. A small number of animal fatalities occurred due to

misapplication into the respiratory tract rather than due to toxicity of the test item. The application of a 10-fold

volume would have increased this risk, especially in young lambs. There were no reported differences

between Merino and Suffolk sheep; both tolerated the treatment equally well. There were no significant

differences detected in the reproductive study.


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8.3 CONCLUSIONS

The pen and field studies demonstrate that Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep

at 1 mL/10 kg bw will be effective for the treatment of control of AAD-sensitive strains of gastro-intestinal

nematodes, including macrocyclic lactone, benzimidazole, levamisole and morantel-resistant strains in

sheep.

The target animal safety studies and efficacy studies demonstrate that the label dose of monepantel is well

tolerated by sheep, including lambs from 2 weeks of age weighing at least 10 kg and breeding ewes and

rams.

The APVMA concludes that Zolvix Monepantel Broad Spectrum Oral Anthelmintic for Sheep would not be

likely to have an unintended effect that is harmful to sheep and would be effective when used according to

label instructions.


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9 LABELLING REQUIREMENTS


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LABELLING REQUIREMENTS 33

HDPE packsizes 0.25L, 0.5L and 1L

Bot t le Label f ront panel

CAUTION

KEEP OUT OF REACH OF CHILDRENREAD SAFETY DIRECTIONS BEFORE OPENING OR USING

FOR ANIMAL TREATMENT ONLY

ZOLVIX

MonepantelBroad Spectrum Oral Anthelmintic for Sheep

Active Constituent: 25 mg/mL Monepantel

Monepantel is a member of the new class of anthelmintics called the Amino-Acetonitrile Derivatives (AADs) and can be used for the treatment and control ofAAD-sensitive strains of gastro-intestinal roundworms (nematodes), includingmacrocyclic lactone, benzimidazole (white), levamisole (clear) and morantel-

resistant strains in sheep.

0.25L, 0.5L, 1L

READ DIRECTIONS FOR USE BEFORE USING THIS PRODUCT

Novartis Animal Health Australasia Pty LimitedACN 076 745 19854 Waterloo RoadNorth Ryde NSW 2113

NOVARTIS ANIMAL HEALTH LOGO

Batch Number:

Expiry Date:


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Bot t le Label back panel

READ THE ATTACHED LEAFLET BEFORE USING THIS PRODUCT

Efficacy spectrum (adult and/or immature L4 stage)

Barbers pole worm Haemonchus contortus, Small brown stomach worm Ostertagia(Teladorsagia) circumcincta,Ostertagia (Teladorsagia) trifurcata

, Ostertagia

(Teladorsagia) davtiani, Black scour worm Trichostrongylus colubriformis,Trichostrongylus vitrinus, Trichostrongylus rugatus;Stomach hair worm Trichostrongylusaxei, Thin necked intestinal worm Nematodirus filicollis

, Nematodirus spathiger(adult

only), Small intestinal worm Cooperia curticei

, Cooperia oncophora

,

Large mouthedbowel worm Chabertia ovina, Large bowel worm Oesophagostomum venulosum(immature L4 only).

Includes adult and immature L4 stage

DIRECTIONS FOR USERestraints:

DO NOT USE in sheep less than 10kg body weight.

DO NOT USE in female sheep which are producing or may in the future producemilk or milk products for human consumption.

Dosage and administrationUse remaining product within 12 months of opening the container.

Re-treatment Interval:DO NOT re-treat less than 21 days after the last treatment. After three consecutivetreatments, 115 days must elapse before treating again with ZOLVIX.

WITHHOLDING PERIODS

MEAT: DO NOT USE less than 14 days before slaughter for human consumption.

MILK: DO NOT USE in female sheep which are producing or may in the futureproduce milk or milk products for human consumption.

EXPORT SLAUGHTER INTERVAL (ESI): DO NOT USE less than 115 days beforeslaughter for export. The ESI on this label was correct at the time of label approval.Before using this product, confirm the current ESI from the manufacturer on 1800633 768 toll free or the APVMA website (www.apvma.gov.au/residues/ESI.shtml).
http://www.apvma.gov.au/residues/ESI.shtmlhttp://www.apvma.gov.au/residues/ESI.shtml


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SAFETY DIRECTIONSMay irritate the eyes. Will irritate the skin. Repeated exposure may cause allergicdisorders. Avoid contact with eyes and skin. If product on skin, immediately wash area withsoap and water. When using the product wear elbow length chemical resistant gloves.Wash hands after use. After each days use wash gloves and contaminated clothing.

FIRST AIDIf poisoning occurs, contact a doctor or Poisons Information Centre (Phone 131126).

StorageStore below 30oC (Room Temperature). Store in the original tightly closed container. Use

remaining product within 12 months of opening the container. Keep out of reach ofchildren.

APVMA Approval No.62752/0.25L/mmyy62752/ 0.5L/mmyy62752/1L/mmyy

NOVARTIS ANIMAL HEALTH AUSTRALASIA PTY LIMITED54 Waterloo RoadNorth Ryde NSW 2113

Registered trademark of Novartis AG, Basel, Switzerland.

BAR CODEDRUMMUSTER LOGO


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Mult if olded zipseal l eafl et f or 0.25L, 0. 5L, 1L (HDPE)

CAUTION

KEEP OUT OF REACH OF CHILDRENREAD SAFETY DIRECTIONS BEFORE OPENING OR USING

FOR ANIMAL TREATMENT ONLY

ZOLVIX

Monepantel

Broad Spectrum Oral Anthelmintic for Sheep

Active Constituent: 25 mg/mL Monepantel

Monepantel is a member of the new class of anthelmintics called the Amino-Acetonitrile Derivatives (AADs) and can be used for the treatment and control ofAAD-sensitive strains of gastro-intestinal roundworms (nematodes), includingmacrocyclic lactone, benzimidazole (white), levamisole (clear) and morantel-

resistant strains in sheep.

0.25L, 0.5L, 1L

READ DIRECTIONS FOR USE BEFORE USING THIS PRODUCT

Novartis Animal Health Australasia Pty LimitedACN 076 745 19854 Waterloo RoadNorth Ryde NSW 2113

NOVARTIS ANIMAL HEALTH LOGO


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ZOLVIX contains MONEPANTEL, a member of the new and unique class of anthelmintics,the Amino-Acetonitrile Derivatives (AADs). When used at the recommended dose rate (2.5mg/kg), it is effective against AAD-sensitive strains of the following gastro-intestinalroundworms (nematodes) including those resistant to macrocyclic lactones,benzimidazoles (white drenches), levamisole and morantel (clear drenches) in sheep.

Efficacy spectrum (adult and/or immature L4 stage)

Barbers pole worm Haemonchus contortus, Small brown stomach worm Ostertagia

(Teladorsagia) circumcincta

,Ostertagia (Teladorsagia) trifurcata

, Ostertagia(Teladorsagia) davtiani, Black scour worm Trichostrongylus colubriformis,Trichostrongylus vitrinus, Trichostrongylus rugatus;Stomach hair worm Trichostrongylusaxei, Thin necked intestinal worm Nematodirus filicollis

, Nematodirus spathiger(adultonly), Small intestinal worm Cooperia curticei, Cooperia oncophora

,Large mouthedbowel worm Chabertia ovina, Large bowel worm Oesophagostomum venulosum(immature L4 only).

Includes adult and immature L4 stage

DIRECTIONS FOR USERestraints:

DO NOT USE in sheep less than 10kg body weight.

DO NOT USE in female sheep which are producing or may in the future producemilk or milk products for human consumption.

Dosage and administration

Use remaining product within 12 months of opening the container. ZOLVIX is a ready-to-use solution. Check dose rates and drench gun before treatment commences. The dose is0.5 mL/ 5 kg (1 mL/10 kg) ZOLVIX liveweight (equivalent to 2.5 mg MONEPANTEL/kgliveweight). Drench sheep orally, using a Novartis recommended drench gun. Maintainapplicator gun carefully to ensure accurate dosage. After use, clean gun by flushing withwarm, soapy water. Rinse with cold water.


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Body weight(kg)

Dose(mL)

No.Treated/

0.25L

No.Treated/

0.5L

No.Treated/1L

No.Treated/

2.5

No.Treated/5L

No.Treated/10L

1015 1.5 166 33

prs_monepantel

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